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Dexanabinol and dexanabinol analogs regulate inflammation related genes

a technology of dexanabinol and dexanabinol, which is applied in the field of pharmaceutical compositions, can solve the problems of pharmacological treatment, unclear mechanisms underlying some therapeutic effects of cannabinoid derivatives, and inability to detect and treat inflammation, so as to prevent, relieve or treat patients

Inactive Publication Date: 2005-06-23
PHARMOS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0041] The pharmaceutical compositions may contain in addition to the active ingredient conventional pharmaceutically acceptable carriers, diluents and excipients necessary to produce a physiologically acceptable and stable formulation.
[0042] The pharmaceutical compositions can be administered by any conventional and appropriate route including oral, parenteral, intravenous, intramuscular, intralesional, subcutaneous, transdermal, intrathecal, rectal or intranasal.
[0043] Prior to their use as medicaments for preventing, alleviating or treating an individual in need thereof, the pharmaceutical compositions will be formulated in unit dosage. The selected dosage of active ingredient depends upon the desired therapeutic effect, the route of administration and the duration of treatment desired.
[0044]

Problems solved by technology

Nevertheless, the mechanisms underlying some therapeutic effects of cannabinoid derivatives remain unclear.
Inflammation is one of the most important processes involved in the defense of an organism; however, when it occurs in some organs, such as brain, in response to an insult, or if it is inappropriate, such as in autoimmune diseases, inflammation can be harmful and therefore requires pharmacological treatment.
Despite the progress in this field, there remains an unmet medical need for effective therapies for inflammatory diseases.
When appropriately regulated and balanced, these agents protect the host by activating defense mechanisms and therefore their complete inhibition is not desirable.
However, if the inflammation is inappropriate and the expression of those mediators is highly dysregulated, then tissue damage may result.

Method used

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  • Dexanabinol and dexanabinol analogs regulate inflammation related genes
  • Dexanabinol and dexanabinol analogs regulate inflammation related genes
  • Dexanabinol and dexanabinol analogs regulate inflammation related genes

Examples

Experimental program
Comparison scheme
Effect test

example 1

RNA Preparation and Real-time RT-PCR

[0140] Total RNA was prepared using SV total RNA isolation system (Promega). The cells or tissues were homogenized in lysis buffer. The lysates were transferred to an RNA isolation column, treated with DNAse, washed and eluted according to kit instructions. RNA concentrations were determined using GeneQuant II (Phamacia-Amersham). Complementary DNA (cDNA) was synthesized from total RNA using SUPERSCRIPT II reverse transcriptase (Life Technologies). 2 μg of total RNA were combined with an oligo (dT)15 primer, 0.5 mM dNTP mix, 8 units of reverse transcriptase and other reaction components up to a final volume of 20 μl according to the kit instructions. The reaction mixture was incubated at 42° C. for 45 min and inactivated at 70° C. for 15 minutes. Quantitative real-time RT-PCR includes 1 μl of the cDNA, 300 nM of the appropriate forward and reverse primers (see below) and 7.5 μl of the reaction mix containing buffer, nucleotides, Taq polymerase an...

example 2

Quantitation of Protein Using ELISA

[0142] The technique used to quantify the amount of a given protein in a liquid sample, either tissue culture supernatant or body fluid, is based on Enzyme Linked ImmunoSorbent Assay (ELISA) methodology. Either commercially available or established in house, the assay is based on the capture of the protein of interest by specific antibodies bound to the bottom of an ELISA plate well. Unbound material is washed away, the captured protein is then exposed to a secondary antibody generally labeled with horseradish peroxidase (HRP) or alkaline phosphatase (ALP). Again the unbound material is washed away, the samples are then incubated with the appropriate substrate yielding a colorimetric reaction. The reaction is stopped and reading is carried out in a spectrophotometer at the appropriate wavelength. Samples are tested at least in duplicate and the appropriate standard curve, consisting of serial dilutions of the recombinant target protein, is incorpo...

example 3

Quantitation of COX-2 Gene Expression in LPS Activated Macrophages and LPS Injected Mice Brains

[0143] We previously showed that dexanabinol and its analogs reduce the levels of secreted PGE2 in LPS activated mouse macrophages (RAW 264.7) cells in vitro (WO 01 / 98289). The IC50 for inhibition of PGE2 secretion were determined and found to be 10 μM, 10 μM, 4 μM, and 8 μM, for dexanabinol, PRS-211,092, PRS-211,095 and PRS-211,220, respectively. For comparison, the IC50 for inhibition of PGE2 secretion for the known anti-inflammatory drugs Celecoxib, Rofecoxib and NS-398 were respectively 5 nM, 100 nM and 100 nM in the same experimental setup. We assumed then that this phenomenon observed at the level of PGE2 secretion was due to direct inhibition of COX-2 enzymatic activity. To check this hypothesis we have now tested in vitro the enzymatic activity of recombinant COX-2 on its substrate in the presence of dexanabinol and its analogs PRS-211,092, PRS-211,095 and PRS-211,220. The assay r...

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Abstract

The present invention relates to methods of treatment utilizing pharmaceutical compositions that include as active ingredients non-psychotropic cannabinoid derivatives that modulate the expression of genes involved in inflammatory and immune processes. Regulating the transcription of pro and anti-inflammatory mediators has useful therapeutic application for prevention and treatment of acute and chronic inflammation, autoimmune diseases and related disorders, pain, infections, liver diseases, cardiovascular disorders, gastrointestinal disorders, disorders of the central and peripheral nervous system including neurodegenerative diseases, respiratory diseases, renal diseases, post-operative complications, tissue rejection and certain types of cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of International application PCT / IL2003 / 000223 filed Mar. 16, 2003, the entire content of which is expressly incorporated herein by reference thereto.FIELD OF THE INVENTION [0002] The present invention relates to pharmaceutical compositions comprising as an active ingredient non-psychotropic cannabinoid derivatives that modulate the expression of genes involved in inflammatory and immune processes. Regulating the transcription of pro and anti-inflammatory mediators has useful therapeutic application for prevention and treatment of acute and chronic inflammation, autoimmune diseases and related disorders, pain, infections, liver diseases, cardiovascular disorders, gastrointestinal disorders, disorders of the central and peripheral nervous system including neurodegenerative diseases, respiratory diseases, renal diseases, post-operative complications, tissue rejection and certain types of cancer. BACKGROU...

Claims

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Application Information

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IPC IPC(8): A61K31/352A61K31/353A61K31/4155A61K31/4178A61K31/453A61K31/4545
CPCA61K31/352A61K31/353A61K31/4545A61K31/4178A61K31/453A61K31/4155
Inventor GARZON, AARONAVRAHAM, AYELETFINK, GEORGE
Owner PHARMOS
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